Deuterated ibrutinib

ABSTRACT

The present invention in one embodiment provides a compound of Formula I: 
                         
or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula I are as defined in the specification.

RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.14/418,831, now U.S. Pat. No. 9,422,295 issued on Aug. 23, 2016, whichis the U.S. National Stage of International Application No.PCT/US2013/052721, which designated the United States and was filed onJul. 30, 2013, published in English, which claims the benefit of U.S.Provisional Application No. 61/677,307, filed on Jul. 30, 2012. Theentire teachings of the above applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Many current medicines suffer from poor absorption, distribution,metabolism and/or excretion (ADME) properties that prevent their wideruse or limit their use in certain indications. Poor ADME properties arealso a major reason for the failure of drug candidates in clinicaltrials. While formulation technologies and prodrug strategies can beemployed in some cases to improve certain ADME properties, theseapproaches often fail to address the underlying ADME problems that existfor many drugs and drug candidates. One such problem is rapid metabolismthat causes a number of drugs, which otherwise would be highly effectivein treating a disease, to be cleared too rapidly from the body. Apossible solution to rapid drug clearance is frequent or high dosing toattain a sufficiently high plasma level of drug. This, however,introduces a number of potential treatment problems such as poor patientcompliance with the dosing regimen, side effects that become more acutewith higher doses, and increased cost of treatment. A rapidlymetabolized drug may also expose patients to undesirable toxic orreactive metabolites.

Another ADME limitation that affects many medicines is the formation oftoxic or biologically reactive metabolites. As a result, some patientsreceiving the drug may experience toxicities, or the safe dosing of suchdrugs may be limited such that patients receive a suboptimal amount ofthe active agent. In certain cases, modifying dosing intervals orformulation approaches can help to reduce clinical adverse effects, butoften the formation of such undesirable metabolites is intrinsic to themetabolism of the compound.

In some select cases, a metabolic inhibitor will be co-administered witha drug that is cleared too rapidly. Such is the case with the proteaseinhibitor class of drugs that are used to treat HIV infection. The FDArecommends that these drugs be co-dosed with ritonavir, an inhibitor ofcytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsiblefor their metabolism (see Kempf, D. J. et al., Antimicrobial agents andchemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverseeffects and adds to the pill burden for HIV patients who must alreadytake a combination of different drugs. Similarly, the CYP2D6 inhibitorquinidine has been added to dextromethorphan for the purpose of reducingrapid CYP2D6 metabolism of dextromethorphan in a treatment ofpseudobulbar affect. Quinidine, however, has unwanted side effects thatgreatly limit its use in potential combination therapy (see Wang, L etal., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67;and FDA label for quinidine at www.accessdata.fda.gov).

In general, combining drugs with cytochrome P450 inhibitors is not asatisfactory strategy for decreasing drug clearance. The inhibition of aCYP enzyme's activity can affect the metabolism and clearance of otherdrugs metabolized by that same enzyme. CYP inhibition can cause otherdrugs to accumulate in the body to toxic levels.

A potentially attractive strategy for improving a drug's metabolicproperties is deuterium modification. In this approach, one attempts toslow the CYP-mediated metabolism of a drug or to reduce the formation ofundesirable metabolites by replacing one or more hydrogen atoms withdeuterium atoms. Deuterium is a safe, stable, non-radioactive isotope ofhydrogen. Compared to hydrogen, deuterium forms stronger bonds withcarbon. In select cases, the increased bond strength imparted bydeuterium can positively impact the ADME properties of a drug, creatingthe potential for improved drug efficacy, safety, and/or tolerability.At the same time, because the size and shape of deuterium areessentially identical to those of hydrogen, replacement of hydrogen bydeuterium would not be expected to affect the biochemical potency andselectivity of the drug as compared to the original chemical entity thatcontains only hydrogen.

Over the past 35 years, the effects of deuterium substitution on therate of metabolism have been reported for a very small percentage ofapproved drugs (see, e.g., Blake, M I et al, J Pharm Sci, 1975,64:367-91; Foster, A B, Adv Drug Res 1985, 14:1-40 (“Foster”); Kushner,D J et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, M B et al, CurrOpin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results havebeen variable and unpredictable. For some compounds deuteration causeddecreased metabolic clearance in vivo. For others, there was no changein metabolism. Still others demonstrated increased metabolic clearance.The variability in deuterium effects has also led experts to question ordismiss deuterium modification as a viable drug design strategy forinhibiting adverse metabolism (see Foster at p. 35 and Fisher at p.101).

The effects of deuterium modification on a drug's metabolic propertiesare not predictable even when deuterium atoms are incorporated at knownsites of metabolism. Only by actually preparing and testing a deuterateddrug can one determine if and how the rate of metabolism will differfrom that of its non-deuterated counterpart. See, for example, Fukuto etal. (J. Med. Chem. 1991, 34, 2871-76). Many drugs have multiple siteswhere metabolism is possible. The site(s) where deuterium substitutionis required and the extent of deuteration necessary to see an effect onmetabolism, if any, will be different for each drug.

SUMMARY OF THE INVENTION

This invention relates to novel derivatives of ibrutinib, an inhibitorof Bruton's tyrosine kinase (BTK) that is under active development forthe treatment of chronic lymphocytic leukemia, mantle cell lymphoma andmultiple myeloma. Ibrutinib may also be useful for treatingnon-Hodgkin's lymphoma, diffuse large B-cell lymphoma, and autoimmunedisease. This invention also provides compositions comprising a compoundof this invention and the use of such compositions in methods oftreating diseases such as the foregoing.

Despite the potential beneficial activities of ibrutinib, there is acontinuing need for new compounds to treat the aforementioned diseasesand conditions.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term “treat” means decrease, suppress, attenuate, diminish, arrest,or stabilize the development or progression of a disease (e.g., adisease or disorder delineated herein), lessen the severity of thedisease or improve the symptoms associated with the disease.

“Disease” means any condition or disorder that damages or interfereswith the normal function of a cell, tissue, or organ.

It will be recognized that some variation of natural isotopic abundanceoccurs in a synthesized compound depending upon the origin of chemicalmaterials used in the synthesis. Thus, a preparation of ibrutinib willinherently contain small amounts of deuterated isotopologues. Theconcentration of naturally abundant stable hydrogen and carbon isotopes,notwithstanding this variation, is small and immaterial as compared tothe degree of stable isotopic substitution of compounds of thisinvention. See, for instance, Wada, E et al., Seikagaku, 1994, 66:15;Gannes, L Z et al., Comp Biochem Physiol Mol Integr Physiol, 1998,119:725.

In the compounds of this invention any atom not specifically designatedas a particular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition. Also unlessotherwise stated, when a position is designated specifically as “D” or“deuterium”, the position is understood to have deuterium at anabundance that is at least 3000 times greater than the natural abundanceof deuterium, which is 0.015% (i.e., at least 45% incorporation ofdeuterium).

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance and the natural abundance of a specifiedisotope.

In other embodiments, a compound of this invention has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium), at least 5500 (82.5%deuterium incorporation), at least 6000 (90% deuterium incorporation),at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation).

The term “isotopologue” refers to a species in which the chemicalstructure differs from a specific compound of this invention only in theisotopic composition thereof.

The term “compound,” when referring to a compound of this invention,refers to a collection of molecules having an identical chemicalstructure, except that there may be isotopic variation among theconstituent atoms of the molecules. Thus, it will be clear to those ofskill in the art that a compound represented by a particular chemicalstructure containing indicated deuterium atoms, will also contain lesseramounts of isotopologues having hydrogen atoms at one or more of thedesignated deuterium positions in that structure. The relative amount ofsuch isotopologues in a compound of this invention will depend upon anumber of factors including the isotopic purity of deuterated reagentsused to make the compound and the efficiency of incorporation ofdeuterium in the various synthesis steps used to prepare the compound.However, as set forth above the relative amount of such isotopologues intoto will be less than 55% of the compound. In other embodiments, therelative amount of such isotopologues in toto will be less than 50%,less than 47.5%, less than 40%, less than 32.5%, less than 25%, lessthan 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, orless than 0.5% of the compound.

The invention also provides salts of the compounds of the invention.

A salt of a compound of this invention is formed between an acid and abasic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functionalgroup. According to another embodiment, the compound is apharmaceutically acceptable acid addition salt.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent that is, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. A “pharmaceuticallyacceptable salt” means any non-toxic salt that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention. A “pharmaceutically acceptable counterion”is an ionic portion of a salt that is not toxic when released from thesalt upon administration to a recipient.

The pharmaceutically acceptable salt may also be a salt of a compound ofthe present invention and a base. Exemplary bases include, but are notlimited to, hydroxide of alkali metals including sodium, potassium, andlithium; hydroxides of alkaline earth metals such as calcium andmagnesium; hydroxides of other metals, such as aluminum and zinc;ammonia, organic amines such as unsubstituted or hydroxyl-substitutedmono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine;pyridine; N-methylamine, N-ethylamine; diethylamine; triethylamine;mono-, bis-, or tris-(2-OH—(C₁-C₆)-alkylamine), such asN,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine;pyrrolidine; and amino acids such as arginine, lysine, and the like.

The compounds of the present invention (e.g., compounds of Formula I),may contain an asymmetric carbon atom, for example, as the result ofdeuterium substitution or otherwise. As such, compounds of thisinvention can exist as either individual enantiomers, or mixtures of thetwo enantiomers. Accordingly, a compound of the present invention mayexist as either a racemic mixture or a scalemic mixture, or asindividual respective stereoisomers that are substantially free fromanother possible stereoisomer. The term “substantially free of otherstereoisomers” as used herein means less than 25% of otherstereoisomers, preferably less than 10% of other stereoisomers, morepreferably less than 5% of other stereoisomers and most preferably lessthan 2% of other stereoisomers are present. Methods of obtaining orsynthesizing an individual enantiomer for a given compound are known inthe art and may be applied as practicable to final compounds or tostarting material or intermediates.

Unless otherwise indicated, when a disclosed compound is named ordepicted by a structure without specifying the stereochemistry and hasone or more chiral centers, it is understood to represent all possiblestereoisomers of the compound.

The term “stable compounds,” as used herein, refers to compounds whichpossess stability sufficient to allow for their manufacture and whichmaintain the integrity of the compound for a sufficient period of timeto be useful for the purposes detailed herein (e.g., formulation intotherapeutic products, intermediates for use in production of therapeuticcompounds, isolatable or storable intermediate compounds, treating adisease or condition responsive to therapeutic agents).

“D” and “d” both refer to deuterium. “d_(x-y)” refers to substitutionwith from x to y number of deuterium atoms. “Stereoisomer” refers toboth enantiomers and diastereomers. “Tert” and “t-” each refer totertiary. “US” refers to the United States of America.

A group is “substituted with” a substituent when one or more hydrogenatoms of the group are replaced with a corresponding number ofsubstituent atoms (if the substituent is an atom) or groups (if thesubstituent is a group). For example, “substituted with deuterium”refers to the replacement of one or more hydrogen atoms with acorresponding number of deuterium atoms.

Throughout this specification, a variable may be referred to generally(e.g., “each Y”) or may be referred to specifically (e.g., Y¹, Y², Y³,etc.). Unless otherwise indicated, when a variable is referred togenerally, it is meant to include all specific embodiments of thatparticular variable.

Therapeutic Compounds

The present invention in one embodiment provides a compound of FormulaI:

or a pharmaceutically acceptable salt thereof, wherein:each Y is independently selected from hydrogen and deuterium,provided that at least one Y is deuterium.

In one embodiment of the compound of Formula I, Y¹², Y¹³, and Y¹⁴ areeach hydrogen. In one aspect of this embodiment, Y⁵ is hydrogen. Inanother aspect, Y⁵ is deuterium. In one aspect of this embodiment, eachY¹ is hydrogen. In another aspect of this embodiment, each Y¹ isdeuterium. In one aspect of this embodiment, each Y² is hydrogen. Inanother aspect, each Y² is deuterium. In one aspect of this embodiment,each Y³ is hydrogen. In another aspect, each Y³ is deuterium. In oneaspect of this embodiment, each Y⁴ is hydrogen. In another aspect, eachY⁴ is deuterium.

In one embodiment of the compound of Formula I, Y¹², Y¹³, and Y¹⁴ areeach deuterium. In one aspect of this embodiment, Y⁵ is hydrogen. Inanother aspect, Y⁵ is deuterium. In one aspect of this embodiment, eachY¹ is hydrogen. In another aspect of this embodiment, each Y¹ isdeuterium. In one aspect of this embodiment, each Y² is hydrogen. Inanother aspect, each Y² is deuterium. In one aspect of this embodiment,each Y³ is hydrogen. In another aspect, each Y³ is deuterium. In oneaspect of this embodiment, each Y⁴ is hydrogen. In another aspect, eachY⁴ is deuterium.

In one embodiment of the compound of Formula I, Y⁵ is hydrogen. In oneaspect of this embodiment, each Y¹ is hydrogen. In another aspect ofthis embodiment, each Y¹ is deuterium. In one aspect of this embodiment,each Y² is hydrogen. In another aspect, each Y² is deuterium. In oneaspect of this embodiment, each Y³ is hydrogen. In another aspect, eachY³ is deuterium. In one aspect of this embodiment, each Y⁴ is hydrogen.In another aspect, each Y⁴ is deuterium.

In one embodiment of the compound of Formula I, Y⁵ is deuterium. In oneaspect of this embodiment, each Y¹ is hydrogen. In another aspect ofthis embodiment, each Y¹ is deuterium. In one aspect of this embodiment,each Y² is hydrogen. In another aspect, each Y² is deuterium. In oneaspect of this embodiment, each Y³ is hydrogen. In another aspect, eachY³ is deuterium. In one aspect of this embodiment, each Y⁴ is hydrogen.In another aspect, each Y⁴ is deuterium.

In one embodiment of the compound of Formula I, each Y¹ is hydrogen. Inone aspect of this embodiment, each Y² is hydrogen. In another aspect,each Y² is deuterium. In one aspect of this embodiment, each Y³ ishydrogen. In another aspect, each Y³ is deuterium. In one aspect of thisembodiment, each Y⁴ is hydrogen. In another aspect, each Y⁴ isdeuterium.

In one embodiment of the compound of Formula I, each Y¹ is deuterium. Inone aspect of this embodiment, each Y² is hydrogen. In another aspect,each Y² is deuterium. In one aspect of this embodiment, each Y³ ishydrogen. In another aspect, each Y³ is deuterium. In one aspect of thisembodiment, each Y⁴ is hydrogen. In another aspect, each Y⁴ isdeuterium.

In one embodiment of the compound of Formula I, each Y² is hydrogen. Inone aspect of this embodiment, each Y³ is hydrogen. In another aspect,each Y³ is deuterium. In one aspect of this embodiment, each Y⁴ ishydrogen. In another aspect, each Y⁴ is deuterium.

In one embodiment of the compound of Formula I, each Y² is deuterium. Inone aspect of this embodiment, each Y³ is hydrogen. In another aspect,each Y³ is deuterium. In one aspect of this embodiment, each Y⁴ ishydrogen. In another aspect, each Y⁴ is deuterium.

In one embodiment of the compound of Formula I, each Y³ is hydrogen. Inone aspect of this embodiment, each Y⁴ is hydrogen. In another aspect,each Y⁴ is deuterium.

In one embodiment of the compound of Formula I, each Y³ is deuterium. Inone aspect of this embodiment, each Y⁴ is hydrogen. In another aspect,each Y⁴ is deuterium.

In one embodiment of the compound of Formula I, each Y⁴ is hydrogen. Inanother embodiment, each Y⁴ is deuterium.

In one embodiment or in one aspect of any of the foregoing embodimentsor aspects, each Y² is hydrogen and each Y⁴ is hydrogen. In anotherembodiment or aspect, each Y² is deuterium and each Y⁴ is deuterium.

In one embodiment or in one aspect of any of the foregoing embodimentsor aspects, each Y⁷ is hydrogen and each Y⁸ is hydrogen. In anotherembodiment or aspect, each Y⁷ is deuterium and each Y⁸ is deuterium.

In yet another embodiment, the compound is a compound of Formula Iselected from any one of the compounds (Cmpd) set forth in Table 1(below):

TABLE 1 Cmpd Y⁷ = Y⁹ = Y¹⁰ = Y¹² = Y¹³ = # Y¹ Y² Y³ Y⁴ Y⁵ Y⁶ Y⁸ Y¹¹ Y¹⁴100 D H H H H H H H H 101 H H H H D H H H H 102 D H H H D H H H H 103 HD H D H H H H H 104 D D H D H H H H H 105 H D H D D H H H H 106 D D H DD H H H H 107 D D D D D H H H H 108 D D H D H D H H H 109 D D D D D D HH H 110 H H H H H D H H H 111 D H H H H H H H D 112 H H H H D H H H D113 D H H H D H H H D 114 H D H D H H H H D 115 D D H D H H H H D 116 HD H D D H H H D 117 D D H D D H H H D 118 D D D D D H H H D 119 D D H DH D H H D 120 D D D D D D H H D 121 H H H H H D H H D 122 H H H H H H HH D 123 H H H H H H D D H 124 H H H H H H D H H 125 H H H H H H H D H126 H H H H H H D D D 127 D D D D D H D D H 128 D D D D D H D D D 129 DD D D D D D D H 130 D D D D D D D D Dor a pharmaceutically acceptable salt thereof, wherein any atom notdesignated as deuterium is present at its natural isotopic abundance.

In another set of embodiments, any atom not designated as deuterium inany of the embodiments, aspects, or examples set forth above is presentat its natural isotopic abundance.

The synthesis of compounds of Formula I may be readily achieved bysynthetic chemists of ordinary skill by reference to the ExemplarySynthesis and Examples disclosed herein. Relevant procedures analogousto those of use for the preparation of compounds of Formula I andintermediates thereof are disclosed, for instance in U.S. Pat. No.7,732,454.

Such methods can be carried out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure.

Exemplary Synthesis

Scheme 1 provides an exemplary procedure for the preparation of thecompounds of Formula I.

As shown in Scheme 1, appropriately deuterated 2 reacts withappropriately deuterated 3 under Mitsunobu reaction conditions in amanner analogous to Zhengying, P. et al., Chem. Med. Chem. 2007, 2,58-61, to provide 4. Deprotection of 4 followed by acylation withappropriately deuterated 5 analogously to US patent publication20080108636 gives a compound of Formula I.

Scheme 2 provides an exemplary procedure for the preparation of thecompounds of formula 2 for use in Scheme 1.

As shown in Scheme 2, 2 may be prepared starting with 6 using aprocedure analogous to what is described in patent publication WO2012003544. 6 is heated with appropriately deuterated 7 to afford 8,which is heated with N-iodosuccinimide to give 9. Reaction of 9 with 10yields 2. A deuterated example of 7, compound 7a (shown in the inset ofScheme 2) is commercially available.

Scheme 3 provides an exemplary procedure for the preparation of thecompounds of formula 10 for use in Scheme 2.

As shown in Scheme 3, appropriately deuterated 11 is treated withappropriately deuterated 12 using a procedure analogous to what isdescribed in patent publication WO 2006125208 to give 17. 17 is treatedwith BuLi followed by B(OiPr)₃ to give 10. A deuterated example of 11,compound 11a (shown in the inset of Scheme 3) is commercially available.A deuterated example of 12, compound 12a (shown in the inset of Scheme3) is commercially available. 11a and/or 12a may be employed in Scheme 3to afford compounds 10a, 10b and 10c.

Scheme 4a provides an exemplary procedure for the preparation ofcompound 3a for use in Scheme 1.

As shown in Scheme 4, 13 is treated with DCl/D₂O to give 14a, which ontreatment with BD₃ gives 15a. Chiral resolution of 15a followed byintroduction of the Boc protecting group is accomplished in a manneranalogous to that described in patent publication WO 2004072086 to give3a.

Scheme 4b provides an exemplary procedure for the preparation ofcompounds 3b-3h for use in Scheme 1.

Compounds 3b-3h, where in each case the positions corresponding to Y⁴and Y² in Formula I are the same, may be prepared as shown in Scheme 4b.According to pathway (i), where each Y⁴ and each Y² is deuterium, 18 isconverted to 19 using a procedure analogous to what is described inSabot, C. et al., J. Org. Chem. 2007, 72, 5001-5004. 19 is treated withNaBY⁵ ₄ followed by BY¹ ₃ to give 15(i). Chiral resolution of 15(i)followed by introduction of the Boc protecting group is accomplished ina manner analogous to that described in patent publication WO 2004072086to give 3(i). According to pathway (ii), where each Y⁴ and each Y² ishydrogen, 18 is treated with NaBY⁵ ₄ followed by BY¹ ₃ to give 15(ii).Chiral resolution of 15(ii) followed by introduction of the Bocprotecting group is accomplished in a manner analogous to that describedin patent publication WO 2004072086 to give 3(ii). Pathway (i) may beused to prepare compounds 3b-3e, while pathway (ii) may be used toprepare compounds 3f-3h (all shown in the inset of Scheme 4b).

Scheme 5 provides an exemplary procedure for the preparation of compound5a for use in Scheme 1.

As shown in Scheme 5, commercially available 16 may be treated withoxalyl chloride to provide 5a in a manner analogous to that described inpatent publication WO 2009005937 A1.

The specific approaches and compounds shown above are not intended to belimiting. The chemical structures in the schemes herein depict variablesthat are hereby defined commensurately with chemical group definitions(moieties, atoms, etc.) of the corresponding position in the compoundformulae herein, whether identified by the same variable name (i.e., R¹,R², R³, etc.) or not. The suitability of a chemical group in a compoundstructure for use in the synthesis of another compound is within theknowledge of one of ordinary skill in the art.

Additional methods of synthesizing compounds of Formula I and theirsynthetic precursors, including those within routes not explicitly shownin schemes herein, are within the means of chemists of ordinary skill inthe art. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing theapplicable compounds are known in the art and include, for example,those described in Larock R, Comprehensive Organic Transformations, VCHPublishers (1989); Greene, T W et al., Protective Groups in OrganicSynthesis, 3^(rd) Ed., John Wiley and Sons (1999); Fieser, L et al.,Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons(1994); and Paquette, L, ed., Encyclopedia of Reagents for OrganicSynthesis, John Wiley and Sons (1995) and subsequent editions thereof.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds.

Compositions

The invention also provides pharmaceutical compositions comprising aneffective amount of a compound of Formula I or pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable salt of saidcompound; and a pharmaceutically acceptable carrier. The carrier(s) are“acceptable” in the sense of being compatible with the other ingredientsof the formulation and, in the case of a pharmaceutically acceptablecarrier, not deleterious to the recipient thereof in an amount used inthe medicament.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

If required, the solubility and bioavailability of the compounds of thepresent invention in pharmaceutical compositions may be enhanced bymethods well-known in the art. One method includes the use of lipidexcipients in the formulation. See “Oral Lipid-Based Formulations:Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs andthe Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare,2007; and “Role of Lipid Excipients in Modifying Oral and ParenteralDrug Delivery: Basic Principles and Biological Examples,” Kishor M.Wasan, ed. Wiley-Interscience, 2006.

Another known method of enhancing bioavailability is the use of anamorphous form of a compound of this invention optionally formulatedwith a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), orblock copolymers of ethylene oxide and propylene oxide. See U.S. Pat.No. 7,014,866; and United States patent publications 20060094744 and20060079502.

The pharmaceutical compositions of the invention include those suitablefor oral, rectal, nasal, topical (including buccal and sublingual),vaginal or parenteral (including subcutaneous, intramuscular,intravenous and intradermal) administration. In certain embodiments, thecompound of the formulae herein is administered transdermally (e.g.,using a transdermal patch or iontophoretic techniques). Otherformulations may conveniently be presented in unit dosage form, e.g.,tablets, sustained release capsules, and in liposomes, and may beprepared by any methods well known in the art of pharmacy. See, forexample, Remington: The Science and Practice of Pharmacy, LippincottWilliams & Wilkins, Baltimore, Md. (20th ed. 2000).

Such preparative methods include the step of bringing into associationwith the molecule to be administered ingredients such as the carrierthat constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers, or both, and then, if necessary, shapingthe product.

In certain embodiments, the compound is administered orally.Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, sachets, or tabletseach containing a predetermined amount of the active ingredient; apowder or granules; a solution or a suspension in an aqueous liquid or anon-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oilliquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatincapsules can be useful for containing such suspensions, which maybeneficially increase the rate of compound absorption.

In the case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozengescomprising the ingredients in a flavored basis, usually sucrose andacacia or tragacanth; and pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween 80) andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this invention may be administered inthe form of suppositories for rectal administration. These compositionscan be prepared by mixing a compound of this invention with a suitablenon-irritating excipient which is solid at room temperature but liquidat the rectal temperature and therefore will melt in the rectum torelease the active components. Such materials include, but are notlimited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art. See, e.g.: Rabinowitz J D and Zaffaroni A C, U.S. Pat. No.6,803,031, assigned to Alexza Molecular Delivery Corporation.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For topicalapplication topically to the skin, the pharmaceutical composition shouldbe formulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches andiontophoretic administration are also included in this invention.

Application of the subject therapeutics may be local, so as to beadministered at the site of interest. Various techniques can be used forproviding the subject compositions at the site of interest, such asinjection, use of catheters, trocars, projectiles, pluronic gel, stents,sustained drug release polymers or other device which provides forinternal access.

Thus, according to yet another embodiment, the compounds of thisinvention may be incorporated into compositions for coating animplantable medical device, such as prostheses, artificial valves,vascular grafts, stents, or catheters. Suitable coatings and the generalpreparation of coated implantable devices are known in the art and areexemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. Thecoatings are typically biocompatible polymeric materials such as ahydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethyleneglycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.The coatings may optionally be further covered by a suitable topcoat offluorosilicone, polysaccharides, polyethylene glycol, phospholipids orcombinations thereof to impart controlled release characteristics in thecomposition. Coatings for invasive devices are to be included within thedefinition of pharmaceutically acceptable carrier, adjuvant or vehicle,as those terms are used herein.

According to another embodiment, the invention provides a method ofcoating an implantable medical device comprising the step of contactingsaid device with the coating composition described above. It will beobvious to those skilled in the art that the coating of the device willoccur prior to implantation into a mammal.

According to another embodiment, the invention provides a method ofimpregnating an implantable drug release device comprising the step ofcontacting said drug release device with a compound or composition ofthis invention. Implantable drug release devices include, but are notlimited to, biodegradable polymer capsules or bullets, non-degradable,diffusible polymer capsules and biodegradable polymer wafers.

According to another embodiment, the invention provides an implantablemedical device coated with a compound or a composition comprising acompound of this invention, such that said compound is therapeuticallyactive.

According to another embodiment, the invention provides an implantabledrug release device impregnated with or containing a compound or acomposition comprising a compound of this invention, such that saidcompound is released from said device and is therapeutically active.

Where an organ or tissue is accessible because of removal from thesubject, such organ or tissue may be bathed in a medium containing acomposition of this invention, a composition of this invention may bepainted onto the organ, or a composition of this invention may beapplied in any other convenient way.

In another embodiment, a composition of this invention further comprisesa second therapeutic agent. The second therapeutic agent may be selectedfrom any compound or therapeutic agent known to have or thatdemonstrates advantageous properties when administered with a compoundhaving the same mechanism of action as ibrutinib. The second agent maybe selected from of atumumab, rituximab, bendamustine, cyclophosphamide,doxorubicin, prednisone, vincristine sulfate, fludarabine, andallopurinol.

In another embodiment, the invention provides separate dosage forms of acompound of this invention and one or more of any of the above-describedsecond therapeutic agents, wherein the compound and second therapeuticagent are associated with one another. The term “associated with oneanother” as used herein means that the separate dosage forms arepackaged together or otherwise attached to one another such that it isreadily apparent that the separate dosage forms are intended to be soldand administered together (within less than 24 hours of one another,consecutively or simultaneously).

In the pharmaceutical compositions of the invention, the compound of thepresent invention is present in an effective amount. As used herein, theterm “effective amount” refers to an amount which, when administered ina proper dosing regimen, is sufficient to treat the target disorder.

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al., Cancer Chemother. Rep, 1966, 50: 219. Body surface area may beapproximately determined from height and weight of the subject. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.

In one embodiment, an effective amount of a compound of this inventioncan range from 1 mg/kg to 50 mg/kg, administered once a day, such as 2.5mg to 50 mg/kg, administered once a day, such as 2.5 mg to 25 mg/kg,administered once a day, such as 5 mg to 25 mg/kg, administered once aday.

In one embodiment, an effective amount of a compound of this inventioncan range from 1 mg/kg to 50 mg/kg, administered twice a day, such as2.5 mg to 50 mg/kg, administered twice a day, such as 2.5 mg to 25mg/kg, administered twice a day, such as 5 mg to 25 mg/kg, administeredtwice a day.

In one embodiment, an effective amount of a compound of this inventioncan range from 50 mg to 5000 mg, such as 100 mg to 2500 mg, such as 100mg to 2250 mg, such as 150 mg to 2250 mg, such as 180 mg to 2250 mg.such as 300 mg to 100 mg, such as 350 mg to 800 mg, such as 400 mg to600 mg, such as 450 mg, which can be administered once a day.

Effective doses will also vary, as recognized by those skilled in theart, depending on the diseases treated, the severity of the disease, theroute of administration, the sex, age and general health condition ofthe subject, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician.

For pharmaceutical compositions that comprise a second therapeuticagent, an effective amount of the second therapeutic agent is betweenabout 20% and 100% of the dosage normally utilized in a monotherapyregime using just that agent. Preferably, an effective amount is betweenabout 70% and 100% of the normal monotherapeutic dose. The normalmonotherapeutic dosages of these second therapeutic agents are wellknown in the art. See, e.g., Wells et al., eds., PharmacotherapyHandbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDRPharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,Tarascon Publishing, Loma Linda, Calif. (2000), each of which referencesare incorporated herein by reference in their entirety.

It is expected that some of the second therapeutic agents referencedabove will act synergistically with the compounds of this invention.When this occurs, it will allow the effective dosage of the secondtherapeutic agent and/or the compound of this invention to be reducedfrom that required in a monotherapy. This has the advantage ofminimizing toxic side effects of either the second therapeutic agent ofa compound of this invention, synergistic improvements in efficacy,improved ease of administration or use and/or reduced overall expense ofcompound preparation or formulation.

Methods of Treatment

In another embodiment, the invention provides a method of inhibiting BTKin a cell, comprising contacting the cell with a compound of Formula Iherein.

According to another embodiment, the invention provides a method oftreating a disease selected from the group consisting of leukemia,including chronic lymphocytic leukemia; lymphoma, including mantle celllymphoma; myeloma, including multiple myeloma; and autoimmune disease,comprising administering a pharmaceutical composition as describedherein. In one embodiment, the disease is selected from the groupconsisting of chronic lymphocytic leukemia, mantle cell lymphoma, andmultiple myeloma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma,and autoimmune disease.

Identifying a subject in need of such treatment can be in the judgmentof a subject or a health care professional and can be subjective (e.g.opinion) or objective (e.g. measurable by a test or diagnostic method).In one embodiment the subject is a patient.

In another embodiment, any of the above methods of treatment comprisesthe further step of co-administering to the subject in need thereof oneor more second therapeutic agents. The choice of second therapeuticagent may be made from any second therapeutic agent known to be usefulfor co-administration with ibrutinib. The choice of second therapeuticagent is also dependent upon the particular disease or condition to betreated. Examples of second therapeutic agents that may be employed inthe methods of this invention are those set forth above for use incombination compositions comprising a compound of this invention and asecond therapeutic agent. Such agents include but are not limited to ofatumumab, rituximab, bendamustine, cyclophosphamide, doxorubicin,prednisone, vincristine sulfate, fludarabine, and allopurinol.

The term “co-administered” as used herein means that the secondtherapeutic agent may be administered together with a compound of thisinvention as part of a single dosage form (such as a composition of thisinvention comprising a compound of the invention and an secondtherapeutic agent as described above) or as separate, multiple dosageforms. Alternatively, the additional agent may be administered prior to,consecutively with, or following the administration of a compound ofthis invention. In such combination therapy treatment, both thecompounds of this invention and the second therapeutic agent(s) areadministered by conventional methods. The administration of acomposition of this invention, comprising both a compound of theinvention and a second therapeutic agent, to a subject does not precludethe separate administration of that same therapeutic agent, any othersecond therapeutic agent or any compound of this invention to saidsubject at another time during a course of treatment.

Effective amounts of these second therapeutic agents are well known tothose skilled in the art and guidance for dosing may be found in patentsand published patent applications referenced herein, as well as in Wellset al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange,Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000),and other medical texts. However, it is well within the skilledartisan's purview to determine the second therapeutic agent's optimaleffective-amount range.

In one embodiment of the invention, where a second therapeutic agent isadministered to a subject, the effective amount of the compound of thisinvention is less than its effective amount would be where the secondtherapeutic agent is not administered. In another embodiment, theeffective amount of the second therapeutic agent is less than itseffective amount would be where the compound of this invention is notadministered. In this way, undesired side effects associated with highdoses of either agent may be minimized. Other potential advantages(including without limitation improved dosing regimens and/or reduceddrug cost) will be apparent to those of skill in the art.

In yet another aspect, the invention provides the use of a compound ofFormula I alone or together with one or more of the above-describedsecond therapeutic agents in the manufacture of a medicament, either asa single composition or as separate dosage forms, for treatment orprevention in a subject of a disease, disorder or symptom set forthabove. Another aspect of the invention is a compound of Formula I foruse in the treatment or prevention in a subject of a disease, disorderor symptom thereof delineated herein.

Example 1. Synthesis of(R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-2,3,3-d₃-1-one(Compound 122)

Step 1. 3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (31)

1H-Pyrazolo[3,4-d]pyrimidin-4-amine, 30 (5.0 g, 37 mmol, 1 equiv) wassuspended in DMF (100 mL) and N-iodosuccinimide (NIS) (10.7 g, 45 mmol,1.2 equiv) was added. The reaction was heated at 80° C. for 2 hours. Thereaction was cooled to room temperature and then to 0° C. and wasquenched by the drop-wise addition of water (200 mL). The resultingsolids were collected by filtration, washed with water and cold ethanol,and dried in a vacuum oven to yield 31 (8.1 g, 84% yield) as a beigesolid.

Step 2. Phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (33)

Compound 31 (4.0 g, 15.3 mmol, 1 equiv), boronic acid 32 (6.56 g, 30.7mmol, 2 equiv), and potassium phosphate tribasic monohydrate (10.56 g,45.9 mmol, 3 equiv) were dissolved in dioxane (50 mL) and water (20 mL).The mixture was sparged with nitrogen for 20 minutes andtetrakis(triphenylphosphine)palladium (2.70 g, 2.3 mmol, 0.15 equiv) wasadded. The mixture was sparged with nitrogen for an additional 5 minutesand then heated at reflux for 24 hours. The reaction was cooled to roomtemperature and stirred overnight, giving a beige precipitate. Thereaction mixture was diluted with water (50 mL) and the solids werecollected by filtration. The crude product was triturated with methanol(150 mL) to yield 3.9 g of 85% pure product. The purity was furtherimproved by trituration with ethyl acetate (100 mL), yielding 33 (3.6 g,77% yield, 90% pure) as a beige solid.

Step 3. (R)-tert-Butyl3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(35)

Compound 33 (1.80 g, 5.9 mmol, 1 equiv), protected piperidine, 34 (1.43g, 7.1 mmol, 1.2 equiv), triphenylphosphine (2.33 g, 8.9 mmol, 1.5equiv), and diisopropyl azodicarboxylate (1.80 g, 8.9 mmol, 1.5 equiv)were dissolved in THF (200 mL) and stirred at room temperatureovernight. The reaction mixture was diluted with ethyl acetate (200 mL)and washed with saturated aqueous sodium bicarbonate (1×300 mL) andbrine (1×300 mL). The organic layer was dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude materialwas adsorbed onto silica gel and purified using an Analogix automatedchromatography system eluting with 0-8% methanol in dichloromethane. Allfractions containing product were combined and re-chromatographed usingthe above conditions to yield 35 (1.1 g, 38% yield) as a white foam.

Step 4.(R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-aminehydrochloride (36)

Compound 35 (700 mg, 1.48 mmol, 1 equiv) was dissolved in dioxane (8mL). A solution of hydrogen chloride in dioxane (4 mL of a 4 N solutionin dioxane, 16 mmol, 10.7 equiv) was added and the reaction was stirredat room temperature overnight. The reaction was diluted with diethylether (20 mL) and the resulting solids were collected by filtrationunder a stream of nitrogen. The product was further dried in a vacuumoven to yield 36 (550 mg, 88% yield) as an off-white solid.

Step 5.(R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-2,3,3-d₃-1-one(Compound 122)

A) DMF (0.003 mL, 0.03 mmol, 0.02 equiv) was added to commerciallyavailable acrylic acid-d₄ (126 mg, 1.66 mmol, 1 equiv, 99 atom % D)followed by oxalyl chloride (0.16 mL, 1.83 mmol, 1.1 equiv). The mixturewas stirred for 30 minutes, at which point all gas evolution had ceased.The resulting acryloyl-d₃ chloride (37) was used as such.

B) In a 20 mL vial, triethylamine (0.46 mL, 3.18 mmol, 3 equiv) wasadded to a suspension of 36 (450 mg, 1.06 mmol, 1 equiv) indichloromethane (10 mL). The reaction was stirred for 15 minutes,resulting in a clear solution. Acryloyl-d₃ chloride (37) (0.10 mL, 1.17mmol, 1.1 equiv, prepared above) was then added and the reaction wasstirred at room temperature for 2 hours. The reaction mixture wasdiluted with dichloromethane (50 mL) and washed with 5% citric acid (50mL). The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude material was purifiedusing an Analogix automated chromatography system eluting with 0-8%methanol in dichloromethane. All fractions containing product werepooled and concentrated to give a colorless film which was dissolved inbenzene/methanol (5 mL) and lyophilized to yield Compound 122 (170 mg,36% yield, [M+H]⁺=444.3) as a white powder.

Example 2. Synthesis of(R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl-6-d₁)piperidin-1-yl)prop-2-en-1-one(Compound 110)

Step 1. 1H-pyrazolo[3,4-d]pyrimidin-4-amine-3,6-d₂ (30a)

A 2 L Parr bomb reactor was charged with 30 (5.0 g, 37 mmol, 1.0 equiv),10% palladium on carbon (500 mg, dry), and D₂O (1 L, 99.8 atom % D). Thereactor was evacuated and backfilled with hydrogen three times. Afterthe final hydrogen charge to 20 psi the mixture was stirred at roomtemperature for 30 minutes. The hydrogen was then evacuated and replacedwith nitrogen. The reactor was heated at 140° C. for 32 hours, at whichpoint the reaction was complete as determined by MS analysis. Thereaction was cooled to room temperature and transferred to a 3 L roundbottom flask. Concentrated HCl (15 mL) was added and the mixture washeated to reflux. Once all of the solid product had dissolved, themixture was filtered hot through a pad of celite, washing with water.While still hot, the pH of the filtrate was adjusted to 8 withconcentrated ammonium hydroxide. The filtrate was cooled to roomtemperature and concentrated under reduced pressure to −50% of theoriginal volume. The resulting white solid was collected by filtrationand dried in a vacuum oven to yield 30a (2.0 g, 40% yield) as a whitesolid. Additional product remained in the filtrate.

Step 2. 3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine-6-d₁ (31a)

Compound 30a (1.0 g, 7.3 mmol, 1 equiv) was suspended in DMF (20 mL) andN-iodosuccinimide (NIS) (1.97 g, 8.7 mmol, 1.2 equiv) was added. Thereaction was heated at 80° C. for 2 hours, an additional portion of NIS(1.0 g) was added and the reaction was heated at 80° C. for another 2hours. The reaction was cooled to room temperature and then to 0° C. andwas quenched by the drop-wise addition of water (60 mL). The resultingsolids were collected by filtration and washed with water. The crudeproduct was purified by trituration with cold ethanol (100 mL) and driedin a vacuum oven to yield 31a (1.74 g, 91% yield) as a beige solid.

Step 3. 3-(4-Phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine-6-d₁(33a)

Compound 31a (1.74 g, 6.6 mmol, 1 equiv), boronic acid 32 (2.85 g, 13.2mmol, 2 equiv), and potassium phosphate tribasic (4.60 g, 19.9 mmol, 3equiv) were dissolved in dioxane (20 mL) and water (8 mL). The mixturewas sparged with nitrogen for 15 minutes andtetrakis(triphenylphosphine)palladium (1.15 g, 1.0 mmol, 0.15 equiv) wasadded. The mixture was sparged with nitrogen for an additional 5 minutesand then heated at reflux for 30 hours.

The reaction was cooled to room temperature and stirred overnight,giving a beige precipitate. The reaction mixture was diluted with water(60 mL) and the solids were collected by filtration. The crude productwas triturated with methanol (50 mL), yielding 33a (900 mg, 45% yield)as a beige solid.

Step 4. (R)-tert-Butyl3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl-6-d₁)piperidine-1-carboxylate(35a)

Compound 33a (840 mg, 2.75 mmol, 1 equiv), protected piperidine 34 (670mg, 3.30 mmol, 1.2 equiv), triphenylphosphine (1.10 g, 4.13 mmol, 1.5equiv), and diisopropyl azodicarboxylate (850 mg, 8.9 mmol, 1.5 equiv)were dissolved in THF (80 mL) and stirred at room temperature overnight.To force the reaction to completion, additional portions of 34 (670 mg),triphenylphosphine (1.10 g), and diisopropyl azodicarboxylate (850 mg)were added and the reaction was stirred an additional 6 hours. Thereaction mixture was concentrated under reduced pressure. The crudematerial was adsorbed onto silica gel and purified using an Analogixautomated chromatography system eluting with 0-8% methanol indichloromethane. All fractions containing product were combined andre-chromatographed using the above conditions to yield 35a (160 mg, 12%yield) as a white solid. Additional less pure fractions were alsorecovered and retained.

Step 5.(R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine-6-d₁hydrochloride (36a)

Compound 35a (160 mg, 0.33 mmol, 1 equiv) was dissolved in dioxane (10mL). A solution of hydrogen chloride in dioxane (2 mL of a 4 N solutionin dioxane, 8 mmol, 24 equiv) was added and the reaction was stirred atroom temperature for 65 hours. The reaction was diluted with diethylether (40 mL) and the resulting solids were collected by filtrationunder a stream of nitrogen. The product was further dried in a vacuumoven to yield 36a (100 mg, 73% yield) as an off-white solid.

Step 6.(R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl-6-d₁)piperidin-1-yl)prop-2-en-1-one(Compound 110)

A) DMF (0.014 mL, 0.18 mmol, 0.02 equiv) was added to acrylic acid (0.24mL, 3.5 mmol, 1 equiv) followed by oxalyl chloride (0.33 mL, 3.8 mmol,1.1 equiv). The mixture was stirred for 30 minutes, at which point allgas evolution had ceased. The resulting acryloyl chloride, 37a, was usedas such.

B) Triethylamine (0.050 mL, 0.36 mmol, 3 equiv) was added to asuspension of 36a (50 mg, 0.12 mmol, 1 equiv) in dichloromethane (2.5mL). The reaction was stirred for 15 minutes, resulting in a clearsolution. Acryloyl chloride, 37a (0.011 mL, 0.13 mmol, 1.1 equiv,prepared above) was added and the reaction was stirred at roomtemperature for 2 hours to yield Compound 110 ([M+H]⁺=442.)

Example 3. Synthesis of(R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl-6-d₃-1-one(Compound 121)

A) DMF (0.002 mL, 0.03 mmol, 0.02 equiv) was added to commerciallyavailable acrylic acid-d₄ (0.10 mL, 1.38 mmol, 1 equiv, 99 atom % D)followed by oxalyl chloride (0.12 mL, 1.52 mmol, 1.1 equiv). The mixturewas stirred for 30 minutes, at which point all gas evolution had ceased.The resulting acryloyl-d₃ chloride, 37, was used as such.

B) Triethylamine (0.050 mL, 0.36 mmol, 3 equiv) was added to asuspension of 36a (50 mg, 0.12 mmol, 1 equiv) in dichloromethane (2.5mL). The reaction was stirred for 15 minutes, resulting in a clearsolution. Acryloyl-d₃ chloride, 37 (0.011 mL, 0.13 mmol, 1.1 equiv,prepared above) was added and the reaction was stirred at roomtemperature for 2 hours to yield Compound 121 ([M+H]⁺=445.)

Example 4. Synthesis of Intermediate (S)-tert-Butyl3-hydroxy-2,2,3,4,4,5,5,6,6-d₉-piperidine-1-carboxylate (3a)

The synthesis of intermediate 3a is shown in Scheme 7 and describedbelow.

Step 1. tert-Butyl 2-oxo-3,3,4,4,5,5-d₆-pyrrolidine-1-carboxylate (41)

Commercially available pyrrolidin-2-one, 40 (5.0 g, 55 mmol, 1 equiv, 98atom % D) and 4-dimethylaminopyridine (740 mg, 6 mmol, 0.11 equiv) weredissolved in acetonitrile and cooled to 0° C. followed by the additionof di-tert-butyl dicarbonate (24.0 g, 110 mmol, 2 equiv). The reactionwas allowed to warm to room temperature and stirred overnight. Thereaction mixture was poured onto water (250 mL) and partiallyconcentrated. The aqueous mixture was extracted with ethyl acetate(3×200 mL). The combined organic layers were washed with 1 N HCl (1×200mL), saturated aqueous sodium bicarbonate (1×200 mL), and brine (1×200mL). The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude product was purifiedusing an Analogix automated chromatography system eluting with 20-80%ethyl acetate in heptanes to yield 41 (10.1 g, 96% yield) as a lightyellow liquid.

Step 2. 4-Oxo-5-dimethylsulfoxonium-pentyl-1,1,2,2,3,3-d₆-carbamic acidtert-butyl ester (42)

Trimethyl sulfoxonium iodide (7.26 g, 33 mmol, 3 equiv) was suspended inTHF (50 mL). Potassium tert-butoxide (5.09 g, 27.5 mmol, 2.5 equiv) wasadded and the reaction was heated at reflux for 2 hours. The whitesuspension was cooled to room temperature and 41 (2.1 g, 11.0 mmol, 1equiv) was added. The reaction was stirred at room temperature for 2hours and quenched by the addition of water (80 mL). The reactionmixture was extracted with 10% isopropanol in dichloromethane (4×100mL). The combined organic layers were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude product wasdissolved in 2:1 ethyl acetate:heptanes (100 mL) and slowly concentratedto approximately 10 mL. The off white precipitate was collected byfiltration, yielding 42 (2.2 g, 68% yield) as an off white solid. ¹H NMRindicated approximately 50% proton incorporation at the 3 position.

Step 3. tert-Butyl 3-oxo-4,4,5,5,6,6-d₆-piperidine-1-carboxylate (43)

Bis(1,5-cyclooctadiene)diiridium(I) dichloride (47 mg, 0.071 mmol, 0.01equiv) was dissolved in 1,2-dichloroethane and the solution was spargedwith nitrogen for 15 minutes and then heated to reflux. In a separateflask, 42 (2.0 g, 7.1 mmol, 1 equiv) was dissolved in 1,2-dichloroethaneand the solution was sparged with nitrogen for 15 minutes. This solutionwas then added drop-wise via syringe pump over 12 hours to the solutionof catalyst at reflux. The reaction was heated at reflux for anadditional hour upon completion of the addition. The reaction was cooledto room temperature and concentrated under reduced pressure. The crudematerial was purified using an Analogix automated chromatography systemeluting with 0-40% ethyl acetate in heptanes to yield 43 (1.1 g, 76%yield) as a thick, colorless oil. ¹H NMR indicated approximately 50%proton incorporation at the 4 position.

Step 4. tert-Butyl 3-oxo-2,2,4,4,5,5,6,6-d₈-piperidine-1-carboxylate(44)

Compound 43 (1.1 g, 5.9 mmol, 1 equiv) was dissolved in chloroform-d(100 mL, 99.8 atom % D) and2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (81 mg, 0.59 mmol,0.1 equiv) was added. The reaction was stirred at room temperature for16 hours, at which point ¹H NMR indicated 10% H remaining at the 2 and 4positions. The solvent was evaporated, fresh chloroform-d was added, andthe reaction was stirred for an additional 16 hours. The cycle was thenrepeated a third time, at which point the reaction was diluted withdichloromethane (100 mL) and washed with 1 N HCl (1×100 mL). The organiclayer was dried over sodium sulfate, filtered, and concentrated underreduced pressure to yield 44 (1.1 g, quantitative recovery) as a thick,colorless oil. No proton signal was detectable at either the 2 or 4position by ¹H NMR.

Step 5. tert-Butyl3-hydroxy-2,2,3,4,4,5,5,6,6-d₉-piperidine-1-carboxylate (45)

Compound 44 (1.1 g, 5.3 mmol, 1 equiv) was dissolved in methanol-d (40mL, 99 atom % D) and cooled to 0° C. Sodium borodeuteride (245 mg, 5.8mmol, 1.1 equiv, 99 atom % D) was added. The reaction was stirred at 0°C. for 2 hours and then at room temperature overnight. The reaction wasquenched with saturated ammonium chloride (5 mL) and water (10 mL). Themixture was partially concentrated and then extracted withdichloromethane (4×50 mL). The combined organic layers were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude material was purified using an Analogix automated chromatographysystem eluting with 0-5% methanol in dichloromethane to yield 45 (0.50g, 46% yield) as a thick, colorless oil which solidified upon standing.

Step 6. 3-Hydroxy-2,2,3,4,4,5,5,6,6-d₉-piperidine (15a)

Compound 45 (0.50 g, 2.4 mmol, 1 equiv) was dissolved in dioxane (5 mL)and hydrogen chloride was added (2 mL of a 4 N solution in dioxane, 8mmol, 3.3 equiv). The reaction was stirred at room temperatureovernight. The crude reaction was then concentrated under reducedpressure and 24% aqueous sodium hydroxide (5 mL) was added to theresidue. The aqueous solution was extracted with 10% isopropanol indichloromethane (6×50 mL). The combined organic layers were dried oversodium sulfate, filtered, and concentrated under reduced pressure toyield 15a (160 mg, 62% yield) as a colorless film.

Step 6. (S)-tert-Butyl3-hydroxy-2,2,3,4,4,5,5,6,6-d₉-piperidine-1-carboxylate (Intermediate3a)

A) Compound 15a (1 equiv) and (R)-camphorsulfonic acid (1 equiv) areheated to reflux in 2-butanone to obtain a clear solution. Upon coolingto room temperature a white solid precipitate is obtained which isfiltered, washed with 2-butanone, and dried to yield the (R)-CSA salt ofthe S enantiomer of 15a. The optical purity is further improved byheating the isolated solid to reflux in a second portion of 2-butanone,cooling, filtering, and drying.

B) The (R)-CSA salt of the S enantiomer of 15a (1 equiv) andtriethylamine (1.2 equiv) are dissolved in dichloromethane and cooled to0° C. Di-tertbutyl dicarbonate (1.1 equiv) is added in one portion andthe reaction is stirred at room temperature for 48 hours. The reactionmixture is diluted with dichloromethane and washed with water. Theorganic layer is dried, filtered, and concentrated. The crude materialis purified by silica gel chromatography to yield 3a (S enantiomer).Intermediate 3a may be useful in the preparation of compounds of FormulaI wherein each Y¹, each Y², each Y³, each Y⁴ and Y⁵ is deuterium, suchas Compounds 107, 109, 118 and 120, in a manner analogous to the oneshown herein for compounds 110, 121 and 122, as a skilled artisan mayreadily envisage. For example, for the preparation of compound 107, thekey intermediates would be compound 3a, 33 and 37a. For the preparationof compound 109, the key intermediates would be compound 3a, 33a and37a. For the preparation of compound 118, the key intermediates would becompound 3a, 33 and 37. And for the preparation of compound 120, the keyintermediates would be compound 3a, 33a and 37.

Example 5. Evaluation of Metabolic Stability

Microsomal Assay:

Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC(Lenexa, Kans.). β-nicotinamide adenine dinucleotide phosphate, reducedform (NADPH), magnesium chloride (MgCl₂), and dimethyl sulfoxide (DMSO)are purchased from Sigma-Aldrich.

Determination of Metabolic Stability:

7.5 mM stock solutions of test compounds are prepared in DMSO. The 7.5mM stock solutions are diluted to 12.5-50 μM in acetonitrile (ACN). The20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 Mpotassium phosphate buffer, pH 7.4, containing 3 mM MgCl₂. The dilutedmicrosomes are added to wells of a 96-well deep-well polypropylene platein triplicate. A 10 μL it aliquot of the 12.5-50 μM test compound isadded to the microsomes and the mixture is pre-warmed for 10 minutes.Reactions are initiated by addition of pre-warmed NADPH solution. Thefinal reaction volume is 0.5 mL and contains 0.5 mg/mL human livermicrosomes, 0.25-1.0 μM test compound, and 2 mM NADPH in 0.1 M potassiumphosphate buffer, pH 7.4, and 3 mM MgCl₂. The reaction mixtures areincubated at 37° C., and 50 μL it aliquots are removed at 0, 5, 10, 20,and 30 minutes and added to shallow-well 96-well plates which contain 50μL it of ice-cold ACN with internal standard to stop the reactions. Theplates are stored at 4° C. for 20 minutes after which 100 μL it of wateris added to the wells of the plate before centrifugation to pelletprecipitated proteins. Supernatants are transferred to another 96-wellplate and analyzed for amounts of parent remaining by LC-MS/MS using anApplied Bio-systems API 4000 mass spectrometer. The same procedure isfollowed for the non-deuterated counterpart of the compound of Formula Iand the positive control, 7-ethoxycoumarin (1 μM). Testing is done intriplicate.

Data Analysis:

The in vitro t_(1/2)s for test compounds are calculated from the slopesof the linear regression of % parent remaining (ln) vs incubation timerelationship.

in vitro t_(1/2)=0.693/k

k=−[slope of linear regression of % parent remaining (ln) vs incubationtime]

Data analysis is performed using Microsoft Excel Software.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the illustrativeexamples, make and utilize the compounds of the present invention andpractice the claimed methods. It should be understood that the foregoingdiscussion and examples merely present a detailed description of certainpreferred embodiments. It will be apparent to those of ordinary skill inthe art that various modifications and equivalents can be made withoutdeparting from the spirit and scope of the invention.

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: each Y¹, eachY², each Y³, each Y⁴, and Y⁵ is deuterium; and Y⁶, each Y⁷, each Y⁸,each Y⁹, each Y¹⁰, Y¹¹, Y¹², Y¹³, and Y¹⁴ is independently selected fromhydrogen and deuterium, wherein any atom not designated as deuterium ispresent at its natural isotopic abundance; and wherein the deuteriumincorporation at each designated deuterium atom is at least 90%.
 2. Thecompound of claim 1, wherein Y¹², Y¹³, and Y¹⁴ are each hydrogen.
 3. Thecompound of claim 1, wherein Y¹², Y¹³, and Y¹⁴ are each deuterium. 4.The compound of claim 1, wherein each Y⁷ is hydrogen and each Y⁸ ishydrogen.
 5. The compound of claim 1, wherein each Y⁷ is deuterium andeach Y⁸ is deuterium.
 6. The compound of claim 1, wherein the deuteriumincorporation at each designated deuterium atom is at least 95%.
 7. Thecompound of claim 1, wherein the deuterium incorporation at eachdesignated deuterium atom is at least 97%.
 8. The compound of claim 1,wherein the compound is selected from any one of the compounds (Cmpd)set forth in the table below: Cmpd Y⁷ = Y⁹ = Y¹⁰ = Y¹² = Y¹³ = # Y¹ Y²Y³ Y⁴ Y⁵ Y⁶ Y⁸ Y¹¹ Y¹⁴ 107 D D D D D H H H H 109 D D D D D D H H H 118 DD D D D H H H D 120 D D D D D D H H D 127 D D D D D H D D H 128 D D D DD H D D D 129 D D D D D D D D H 130 D D D D D D D D D

or a pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition comprising the compound of claim 1 or a pharmaceuticallyacceptable salt thereof; and a pharmaceutically acceptable carrier. 10.A method of inhibiting BTK in a cell, comprising contacting the cellwith a compound of claim
 1. 11. A method of treating a disease selectedfrom the group consisting of chronic lymphocytic leukemia, mantle celllymphoma, and multiple myeloma, comprising administering to a subject inneed of such treatment a compound of claim 1.